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Roberto Testi, Professor and Chair in Immunology

April 24, 2012 

BabelFAmily: Dr. Testi, you are one of the foremost doctors researching possible Friedreich's Ataxia treatments and cures.  As such, we wanted to conduct an interview with you to share news of your progress with our global readers and audience. And, it may be a little late but, we want to congratulate you on being a winner of the fourth prestigious Advanced Grants 2011 competition from the European Research Council for your Friedriech's Ataxia research.
Can you tell us about your interest in FA and how you became involved in this rare disease from a research perspective?

Dr. Testi: My scientific interest has been focused on the molecular basis of receptor signal transduction and cell death programs, including mitochondrial cell death, for many years. About 10 years ago I decided to focus on a specific disease in which mitochondrial cell death was playing a role. Among the potential candidates, Friedreich’s ataxia was particularly interesting because of its relative simplicity (defined, single gene defect), the appeal of a primordial and mysterious protein (frataxin) and, most of all, the urgent need of a therapy. So I progressively redirected 100% of the efforts of my group to FA research.

BabelFAmily: How many different projects are you working on around FA research?

Dr. Testi: Currently, my lab counts 15 among staff scientists, postdocs, and PhD students. It is mainly focused on three projects with direct therapeutic focus: 1) the development of small molecule inhibitors of frataxin ubiquitination, 2) identification of the frataxin E3 ubiquitin ligase and development of small molecule inhibitors of the E3 ligase, and 3) development of novel strategies for therapeutic protein transfer of frataxin. Also, we are interested in understanding the molecular mechanisms that control interferon gamma-induced frataxin accumulation, and in understanding the biological role of specific posttranslational modifications of frataxin.

BabelFAmily: Your first published article related to FA discusses extramitochondrial frataxin and its potential role in cell survival. Are you still considering manipulation with extramitochondrial frataxin as a possible therapeutic target? Are you still working on this?

Dr. Testi: We find extramitochondrial frataxin in a few unexpected and interesting subcellular locations. We are clearly still working on this as we believe this can be exploited therapeutically.

BabelFAmily: We read that you are working on new set of compounds that are acting on the ubiquitin- proteasome system of frataxin degradation. Can you provide us with an update of this work? Are you working with a pharmaceutical company on this set of compounds?

Dr. Testi: We are now developing small molecule inhibitors of frataxin ubiquitination that appear more effective than those we previously described, at least in vitro. Our goal is to test the more promising leads in the GAA-frataxin animal model of the disease, as soon as appropriate. We are not collaborating with any pharmaceutical company at the moment, but we might in the future.

BabelFAmily: As we have understood from published articles, the discovery that Interferon Gamma upregulates frataxin levels came as a surprise. Can you explain how your newer research focused on Interferon Gamma upregulation of frataxin differs from your past research around small molecule therapeutics? Can you tell us more about  this work?

Dr. Testi: The development of small molecule inhibitors of frataxin ubiquitination is aimed at designing pharmaceutical compounds that act by blocking the physiologic ubiquitination of the frataxin precursor, thus preventing its targeting to and degradation by the proteasome. This should allow more precursor to enter the mitochondria and be processed to mature frataxin. The interferon gamma work originated instead by our independent observation that cells derived from FA patients fail to express an interferon gamma-inducible component of the immunoproteasome. We found that exposure to interferon gamma was able to re-induce the expression of this protein in FA cells, but unexpectedly it also upregulated frataxin. We then confirmed that interferon gamma was capable to induce frataxin in primary cells derived from FA patients. The subsequent collaboration with the group led by Dr. Mark Pook, Brunel University, Uxbridge UK, was instrumental to demonstrate, in the GAA-frataxin animal model of the disease, that treatment with interferon gamma is sufficient to upregulate frataxin in frataxin-defective dorsal root ganglia neurons and to ameliorate sensorimotor performances of ill mice.

BabelFAmily: What are your next steps in Interferon Gamma research? Are there any clinical trials planned? Are there any pharmaceutical companies interested in this research?

Dr. Testi: We are planning to start a pilot Phase II clinical in the fall of 2012. This trial is aimed at verifying whether the subcutaneous injection of interferon gamma is safe and well tolerated by FA patients and whether it is capable of inducing frataxin upregulation. The clinical trial will enroll a small cohort of FA patients which will receive a three months treatment. We are not collaborating with any pharmaceutical company at the moment, but we might in the future.

BabelFAmily: Can you explain more about your FAST project? What are the new therapeutic targets this project will research? Is this project connected with your work on ubiquitin-proteasome degradation of frataxin, or with Interferon Gamma?

Dr. Testi: The Friedreich Ataxia Seeks Therapy (FAST) project funded by the European Research Council is exclusively focused on the development of inhibitors of frataxin ubiquitination, targeting either frataxin or the frataxin E3 ubiquitin ligase, and on their pre-clinical testing in the GAA-frataxin animal model.

BabelFAmily: From your perspective, how far are we from a first high-impact therapy for FA?

Dr. Testi: There is a growing number of highly promising therapeutic approaches to FA currently being tested. As far as interferon gamma is concerned, a success of the pilot clinical trial will clearly encourage the launch of large controlled clinical trials in 2013 aimed at verifying therapeutic efficacy in FA patients. Due to the clinical complexity of the disease, however, it is hard to predict if and when such trials may deliver positive or even conclusive results. Of course we hope they will.

BabelFAmily: Thank you for taking the time for an interview on behalf of BabelFAmily and all FA patients and families around the world. We thank you for your ongoing work towards finding treatments and a cure.

Dr. Testi: Thank you for your interest and support to our work.